Observational Fear Research Articles

Understanding Others' Distress Through Past Experiences: The Role of Memory Engram Cells in Observational Fear.

For individuals to survive and function in society, it is essential that they recognize, interact with, and learn from other conspecifics. Observational fear (OF) is the well-conserved empathic ability of individuals to understand the other's aversive situation. While it is widely known that factors such as prior similar aversive experience and social familiarity with the demonstrator facilitate OF, the neural circuit mechanisms that explicitly regulate experience-dependent OF (Exp OF) were unclear. In this review, we examine the neural circuit mechanisms that regulate OF, with an emphasis on rodent models, and then discuss emerging evidence for the role of fear memory engram cells in the regulation of Exp OF. First, we examine the neural circuit mechanisms that underlie Naive OF, which is when an observer lacks prior experiences relevant to OF. In particular, the anterior cingulate cortex to basolateral amygdala (BLA) neural circuit is essential for Naive OF. Next, we discuss a recent study that developed a behavioral paradigm in mice to examine the neural circuit mechanisms that underlie Exp OF. This study found that fear memory engram cells in the BLA of observers, which form during a prior similar aversive experience with shock, are reactivated by ventral hippocampal neurons in response to shock delivery to the familiar demonstrator to elicit Exp OF. Finally, we discuss the implications of fear memory engram cells in Exp OF and directions of future research that are of both translational and basic interest.

Ventromedial prefrontal neurons represent self-states shaped by vicarious fear in male mice

Perception of fear induced by others in danger elicits complex vicarious fear responses and behavioral outputs. In rodents, observing a conspecific receive aversive stimuli leads to escape and freezing behavior. It remains unclear how these behavioral self-states in response to others in fear are neurophysiologically represented. Here, we assess such representations in the ventromedial prefrontal cortex (vmPFC), an essential site for empathy, in an observational fear (OF) paradigm in male mice. We classify the observer mouse’s stereotypic behaviors during OF using a machine-learning approach. Optogenetic inhibition of the vmPFC specifically disrupts OF-induced escape behavior. In vivo Ca2+ imaging reveals that vmPFC neural populations represent intermingled information of other- and self-states. Distinct subpopulations are activated and suppressed by others’ fear responses, simultaneously representing self-freezing states. This mixed selectivity requires inputs from the anterior cingulate cortex and the basolateral amygdala to regulate OF-induced escape behavior.

Hippocampal-amygdala memory circuits govern experience-dependent observational fear.

The empathic ability to vicariously experience the other's fearful situation, a process called observational fear (OF), is critical to survive in nature and function in society. OF can be facilitated by both prior similar fear experience in the observer and social familiarity with the demonstrator. However, the neural circuit mechanisms of experience-dependent OF (Exp OF) remain unknown. Here, we demonstrate that hippocampal-basolateral amygdala (HPC-BLA) circuits in mice without involving the anterior cingulate cortex, considered a center of OF, mediate Exp OF. Dorsal HPC neurons generate fear memory engram cells in BLA encoding prior similar fear experiences, which are essential for Exp OF. On the other hand, ventral HPC neurons respond to the familiar demonstrator's aversive situation during Exp OF, which reactivates the fear memory engram cells in BLA to elicit Exp OF. Our study provides new insights into the memory engram-dependent perception-action coupling that underlies empathic behaviors like Exp OF.

Activation of parvalbumin interneurons in anterior cingulate cortex impairs observational fear

The ability to detect conspecific’s distress is crucial for animal survival. In rodent models, observational fear (OF) occurs when one animal perceives another fear related negative emotions, which may model certain behaviors caused by witnessing traumatic experiences in humans. Anterior cingulate cortex (ACC) has been showed to play a crucial role in OF. However, cellular and neural circuit basis relating to ACC governing OF is poorly understood. Here, we used Designer Receptor Exclusively Activated by a Designer Drug (DREADD) system to investigate the cell type specific circuit mechanism of ACC in OF. Firstly, inhibitory hM4D (Gi) designer receptor together with clozapine N-oxide (CNO) injection was applied to inactivate ACC neurons in the observer mice. We found that, chemogenetic inhibition of ACC resulted in a decreased freezing response in the observer mice. Next, combining PV-ires-Cre mice and Cre-dependent DREADD system, we selectively targeted the ACC parvalbumin (PV) interneurons with the excitatory hM3D (Gq) designer receptor. Activation of ACC PV interneurons following CNO injection reduced freezing response in the observer mice, while had no effect on freezing response in the demonstrator mice. Finally, monosynaptic rabies retrograde tracing revealed that ACC PV interneurons receive inputs from the mediodorsal thalamic nucleus (MD) and the ventromedial thalamic nucleus (VM), both known for their roles in OF. Taken together, these findings reveal that ACC activation is important for OF, during which PV interneurons in ACC play an important regulatory role. Abnormal function of ACC PV interneurons might contribute to the pathology of empathy- deficits related diseases, such as autism and schizophrenia.

GABAb Receptor Mediates Opposing Adaptations of GABA Release From Two Types of Prefrontal Interneurons After Observational Fear.

The observational fear (OF) paradigm in rodents, in which the subject is exposed to a distressed conspecific, elicits contextual fear learning and enhances future passive avoidance learning, which may model certain behavioral traits resulting from traumatic experiences in humans. As these behaviors affected by the OF require dorso-medial prefrontal cortex (dmPFC), we searched for synaptic adaptations in dmPFC resulting from OF in mice by recording synaptic responses in dmPFC layer V pyramidal neurons elicited by repeated 5 Hz electrical stimulation of dmPFC layer I or by optogenetic stimulation of specific interneurons ex vivo 1 day after OF. OF increased depression of inhibitory postsynaptic currents (IPSCs) along IPSC trains evoked by the 5 Hz electrical stimulation, but, surprisingly, decreased depression of dendritic IPSCs isolated after blocking GABAa receptor on the soma. Subsequent optogenetic analyses revealed increased depression of IPSCs originating from perisomatically projecting parvalbumin interneurons (PV-IPSCs), but decreased depression of IPSCs from dendritically projecting somatostatin cells (SOM-IPSCs). These changes were no longer detectable in the presence of a GABAb receptor antagonist CGP52432. Meanwhile, OF decreased the sensitivity of SOM-IPSCs, but not PV-IPSCs to a GABAb receptor agonist baclofen. Thus, OF causes opposing changes in GABAb receptor mediated suppression of GABA release from PV-positive and SOM-positive interneurons. Such adaptations may alter dmPFC connectivity with brain areas that target its deep vs superficial layers and thereby contribute to the behavioral consequences of the aversive experiences.

Variability in empathic fear response among 11 inbred strains of mice.

Empathy is an important emotional process that involves the ability to recognize and share emotions with others. We have previously developed an observational fear learning (OFL) behavioral assay to measure empathic fear in mice. In the OFL task, a mouse is conditioned for context-dependent fear when it observes a conspecific demonstrator receiving aversive stimuli. In the present study, by comparing 11 different inbred mouse strains that are commonly used in the laboratory, we found that empathic fear response was highly variable between different strains. Five strains--C57BL/6J, C57BL/6NTac, 129S1/SvImJ, 129S4/SvJae and BTBR T(+) Itpr3(tf) /J--showed observational fear (OF) responses, whereas AKR/J, BALB/cByJ, C3H/HeJ, DBA/2J, FVB/NJ and NOD/ShiLtJ mice exhibited low empathic fear response. Importantly, day 2 OF memory was significantly correlated with contextual memory in the classical fear conditioning among the 11 strains. Innate differences in anxiety, locomotor activity, sociability and preference for social novelty were not significantly correlated with OFL. Interestingly, early adolescent C57BL/6J mice exhibited an increase in acquisition of OF. The level of OFL in C57BL/6J strain was not affected by sex or strains of the demonstrator. Taken together, these data strongly suggest that there are naturally occurring OFL-specific genetic variations modulating empathic fear behaviors in mice. The identification of causal genes may uncover novel genetic pathways and underlying neural mechanisms that modulate empathic fear and, ultimately, provide new targets for therapeutic intervention in human mental disorders associated with impaired empathy.

Learning to fear what others have feared before

Learning to fear what others have feared before